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Veterinary Oncology

Cancer is an uncontrolled growth of abnormal cells. It is found in animals as well as humans. There are many different types of cancer that are found in animals, symptoms are often similar to those in people (eg. abnormal swelling, unexplained weight loss, lethargy / reluctance to exercise etc). Cancer is one of the leading causes of death in companion animals such as dogs and cats, it is particularly common in animals that live 10 years or longer. If treatment is appropriate this may include chemotherapy and surgery or radiotherapy.

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Veterinary Oncology Links
Recent Publications

Veterinary Oncology Links (11 links)

Recent Publications

Yoel U, Gopas J, Ozer J, et al.
Canine Scent Detection of Volatile Elements, Characteristic of Malignant Cells, in Cell Cultures.
Isr Med Assoc J. 2015; 17(9):567-70 [PubMed] Related Publications
BACKGROUND: In recent years several reports have been published describing dogs' ability to detect, by scent, patients with cancer. This ability is based on the sniffing of volatile organic elements that are secreted by malignant cells or react to them.
OBJECTIVES: To evaluate the ability of trained dogs to detect breast cancer cell cultures (MCF7) compared to the control pseudo-normal keratinocyte cell line (HaCaT), and to detect melanoma (BG) and type 2 epithelial lung carcinoma (A549) malignant cell cultures to which they were not previously exposed in the course of their training.
METHODS: Cell cultures were prepared in a standard manner. Two Belgian Shepherd dogs were trained and then tested in a single-blind test (for dogs and trainers) on their ability to detect the "target specimen," a MCF7 breast cancer cell culture. Following this, the ability of the dogs to detect cancer cell cultures that they were not previously exposed to (i.e., A549, BG) was tested. In each test round, four specimens placed in identical blocks were arranged in a line with one meter between them: one target specimen (MCF7, A549, BG), two control specimens (HaCaT), and a sample containing cell culture medium only.
RESULTS: The two dogs picked out all the target specimens of MCF7 breast cancer cell cultures that they were trained to detect (10/10) as well as all the target specimens that they were not previously exposed to [A549 (5/5) and BG (5/5)], but did not pick out the control specimens or the cell culture medium. Thus, the sensitivity, specificity, and positive and negative predictive values for both dogs were 100%.
CONCLUSIONS: The results of this study support the assumption that cancer cells have a unique odor pattern, and that this odor pattern is common to different types of cancer.

Zorzan E, Hanssens K, Giantin M, et al.
Mutational Hotspot of TET2, IDH1, IDH2, SRSF2, SF3B1, KRAS, and NRAS from Human Systemic Mastocytosis Are Not Conserved in Canine Mast Cell Tumors.
PLoS One. 2015; 10(11):e0142450 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Both canine cutaneous mast cell tumor (MCT) and human systemic mastocytosis (SM) are characterized by abnormal proliferation and accumulation of mast cells in tissues and, frequently, by the presence of activating mutations in the receptor tyrosine kinase V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (c-KIT), albeit at different incidence (>80% in SM and 10-30% in MCT). In the last few years, it has been discovered that additional mutations in other genes belonging to the methylation system, the splicing machinery and cell signaling, contribute, with c-KIT, to SM pathogenesis and/or phenotype. In the present study, the mutational profile of the Tet methylcytosine dioxygenase 2 (TET2), the isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2), the serine/arginine-rich splicing factor 2 (SRSF2), the splicing factor 3b subunit 1 (SF3B1), the Kirsten rat sarcoma viral oncogene homolog (KRAS) and the neuroblastoma RAS viral oncogene homolog (NRAS), commonly mutated in human myeloid malignancies and mastocytosis, was investigated in canine MCTs.
METHODS: Using the Sanger sequencing method, a cohort of 75 DNA samples extracted from MCT biopsies already investigated for c-KIT mutations were screened for the "human-like" hot spot mutations of listed genes.
RESULTS: No mutations were ever identified except for TET2 even if with low frequency (2.7%). In contrast to what is observed in human TET2 no frame-shift mutations were found in MCT samples.
CONCLUSION: Results obtained in this preliminary study are suggestive of a substantial difference between human SM and canine MCT if we consider some target genes known to be involved in the pathogenesis of human SM.

Dhawan D, Paoloni M, Shukradas S, et al.
Comparative Gene Expression Analyses Identify Luminal and Basal Subtypes of Canine Invasive Urothelial Carcinoma That Mimic Patterns in Human Invasive Bladder Cancer.
PLoS One. 2015; 10(9):e0136688 [PubMed] Free Access to Full Article Related Publications
More than 160,000 people are expected to die from invasive urothelial carcinoma (iUC) this year worldwide. Research in relevant animal models is essential to improving iUC management. Naturally-occurring canine iUC closely resembles human iUC in histopathology, metastatic behavior, and treatment response, and could provide a relevant model for human iUC. The molecular characterization of canine iUC, however, has been limited. Work was conducted to compare gene expression array results between tissue samples from iUC and normal bladder in dogs, with comparison to similar expression array data from human iUC and normal bladder in the literature. Considerable similarities between enrichment patterns of genes in canine and human iUC were observed. These included patterns mirroring basal and luminal subtypes initially observed in human breast cancer and more recently noted in human iUC. Canine iUC samples also exhibited enrichment for genes involved in P53 pathways, as has been reported in human iUC. This is particularly relevant as drugs targeting these genes/pathways in other cancers could be repurposed to treat iUC, with dogs providing a model to optimize therapy. As part of the validation of the results and proof of principal for evaluating individualized targeted therapy, the overexpression of EGFR in canine bladder iUC was confirmed. The similarities in gene expression patterns between dogs and humans add considerably to the value of naturally-occurring canine iUC as a relevant and much needed animal model for human iUC. Furthermore, the finding of expression patterns that cross different pathologically-defined cancers could allow studies of dogs with iUC to help optimize cancer management across multiple cancer types. The work is also expected to lead to a better understanding of the biological importance of the gene expression patterns, and the potential application of the cross-species comparisons approach to other cancer types as well.

Okada S, Furuya M, Takenaka S, et al.
Localization of heat shock protein 110 in canine mammary gland tumors.
Vet Immunol Immunopathol. 2015; 167(3-4):139-46 [PubMed] Related Publications
Heat shock proteins (HSPs) function as molecular chaperones in the regulation of protein folding, conformation, and assembly; in addition, they also protect cells from protein-protein aggregation resulting from cellular stress. Recently, HSPs were shown to be overexpressed in several human cancer cells compared with normal cells. HSPs are considered to be related to apoptosis-associated proteins, and inhibition of apoptosis promotes tumor growth. Canine mammary gland tumors have received a great deal of attention from researchers due to the many common biological and histological characteristics that they share with human tumors. We previously confirmed that HSP110 is a canine mammary gland tumor antigen and reported that HSP110 mRNA expression significantly increased in tumor tissue. We have now created a functional recombinant canine HSP110 protein and a rabbit anti-HSP110 polyclonal antibody. This recombinant protein can refold heat-denatured firefly luciferase at 42°C. Immunohistochemical analysis showed that HSP110 was mainly localized in the cytoplasm of epithelial and interstitial cells in canine mammary gland tumors. Extensive genomic research has revealed genetic similarities between humans and dogs; comparative oncological studies between these species have made remarkable progress. The results reported here contribute valuable oncological knowledge for the development of novel therapeutic methods in both veterinary science and human medicine.

Zhang Q, Gao H, He Q
Taming Cell Penetrating Peptides: Never Too Old To Teach Old Dogs New Tricks.
Mol Pharm. 2015; 12(9):3105-18 [PubMed] Related Publications
Cell penetrating peptides (CPPs) have received substantial attention due to their intrinsic property to cross plasma membranes or even as helpers to facilitate the cellular entry of drug molecules, macromolecules, and nanoparticles. Although CPPs and CPP-like peptides provided versatile platforms for drug delivery, their nonselectivity or lack of delivery efficiency is stirring up debates as to the tactics for the optimizing the CPPs themselves. The good news is that, as spurred by the recent progress in the understanding of tumor microenvironment as well as biochemistry and material sciences, we have made attempts in working on perfecting or even "taming" CPPs and CPP-functionalized drug vectors for tumor delivery, and some of them afforded gratifying results. Due to the fact that these peptides are mainly short peptides made up of amino acids (5-30 amino acids), the addition, modification, or replacement of amino acids might lead to surprisingly improved performance. Several novel environment-responsive CPPs or CPP-like peptides have also been discovered. In this review we will discuss the measures taken to harness the power of CPPs and the discovery of environment-responsive peptides with CPP properties.

Jarmusch AK, Kerian KS, Pirro V, et al.
Characteristic lipid profiles of canine non-Hodgkin's lymphoma from surgical biopsy tissue sections and fine needle aspirate smears by desorption electrospray ionization--mass spectrometry.
Analyst. 2015; 140(18):6321-9 [PubMed] Related Publications
Canine non-Hodgkin's lymphoma (NHL) is a heterogeneous group of cancers representing approximately 15% of all canine cancers. Further, canine NHL mimics human disease in regards to histopathology and clinical behavior and could function as a comparative model. Diagnosis is currently performed by histopathological evaluation of surgical biopsy specimens and fine needle aspirate (FNA) cytology, an alternative and less invasive method for diagnosis. Desorption electrospray ionization - mass spectrometry (DESI-MS) imaging was performed on tissue sections of surgical biopsies and FNA smears. Mass spectra acquired from normal lymph nodes and NHL tumors were explored using multivariate statistics (e.g. principal component analysis). Tissue sections yielded a predicted sensitivity of 100% for normal and 93.1% for tumor. Further, preliminary results suggest B-cell and T-cell lymphoma can be discriminated (CV sensitivity of 95.5% and 85.7%, respectively). Normal and B-cell NHL FNA samples analyzed by DESI produced spectra that were similar to spectra obtained from surgical biopsies. FNA samples were evaluated using a PCA-LDA classification system built using tissue section data, exploring if the chemical information obtained from the different sample types is similar and whether DESI-MS performed on FNA samples is of diagnostic value. FNA prediction rate for normal (85.7%) and B-cell NHL (89.3%) indicated that DESI-MS analysis of FNA, not previously explored, could provide rapid preliminary diagnosis. Certainly, MS provides complementary molecular information to be used in conjunction with histopathology/cytology, potentially improving diagnostic confidence. The methodology outlined here is applicable to canine NHL, further supports canine models of human NHL, and translation to humans is envisioned.

Noguchi S, Mori T, Nakagawa T, et al.
DNA methylation contributes toward silencing of antioncogenic microRNA-203 in human and canine melanoma cells.
Melanoma Res. 2015; 25(5):390-8 [PubMed] Related Publications
Melanoma is a poor-prognosis cancer in both humans and dogs. We have elucidated the antitumor mechanisms of antioncogenic microRNA (miR)-203 which is downregulated in human melanoma, as well as in canine melanoma. The aim of this study was to clarify the mechanism of this downregulation. We focused on epigenetic aberration of miR-203 transcription. Treatment with 5-aza-2'-deoxycitidine (5-aza) markedly upregulated the expression level of miR-203 in almost all of the cell lines tested. Furthermore, bisulfite sequencing or methylation-specific PCR showed DNA methylation of CpG islands upstream of the miR-203 coding region (MIR203) in both human and canine melanoma cells, as well as in canine clinical specimens, but not in human normal melanocytes. The results of a luciferase activity assay showed obvious suppression of the transcription of miR-203 by DNA methylation. The use of the luciferase activity assay for CREB1 and an inhibition assay of miR-203 function performed with an miR-203 inhibitor confirmed the contribution of miR-203 upregulation toward the negative regulation of the target gene of miR-203. These results indicate that canine melanoma might be a preclinical model of human melanoma for epigenetic studies. In addition, this study suggests that agents that can demethylate MIR203 could be a common promising therapeutic agent for the treatment of human and canine melanomas.

Khanna C, Rosenberg M, Vail DM
A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs.
J Vet Intern Med. 2015 Jul-Aug; 29(4):1006-12 [PubMed] Free Access to Full Article Related Publications
Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol(®) for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase-anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.

de Araújo MR, Campos LC, Ferreira E, Cassali GD
Quantitation of the Regional Lymph Node Metastatic Burden and Prognosis in Malignant Mammary Tumors of Dogs.
J Vet Intern Med. 2015 Sep-Oct; 29(5):1360-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As in women, regional lymph node status impacts survival in dogs with malignant mammary tumors. However, few studies have evaluated regional lymph node metastases in dogs with malignant mammary gland tumors.
OBJECTIVES: To estimate overall survival based on the assessments of the lymph node status and the morphologic and morphometric features in female dogs with malignant mammary gland tumors.
MATERIALS AND METHODS: In total, 178 lymph nodes from 97 female dogs were assessed and reviewed, and after confirmation by immunohistochemistry (IHC), 161 lymph nodes were selected for analysis of metastases. Animals were considered metastasis-free (negative lymph nodes) only after IHC analysis for cytokeratin AE1/AE3. The number of positive lymph nodes, the number of metastatic foci, the maximum diameter and the area of metastasis were analyzed, and estimates of overall survival were made.
RESULTS: Dogs with metastasis had lower mean survival than those with metastasis-free regional lymph nodes, showing a direct relationship between the number of affected lymph nodes and shorter survival. However, histologic analysis of the lymph nodes identified lower survival rates in animals with macrometastases and isolated tumor cells, areas of metastasis >20.11 mm², and metastatic diameters >7.32 mm.
CONCLUSION: The identification of ≥1 lymph nodes positive for metastasis and morphometric characterization of lymphatic metastases indicate the prognostic relevance of lymph nodes status in dogs with mammary tumors.

Brooks SW, Moore DR, Marzouk EB, et al.
Canine olfaction and electronic nose detection of volatile organic compounds in the detection of cancer: a review.
Cancer Invest. 2015; 33(9):411-9 [PubMed] Related Publications
Olfactory cancer detection shows promise as an affordable, precise, and noninvasive way to screen for cancer. This review focuses on two methods of olfactory cancer detection: first, the ability of canines to differentiate between cancerous and healthy individuals through the use of biological samples and second, electronic nose technology that uses chemical sensors to detect known biomarkers in exhaled breath. This review summarizes and critiques past research and outlines future directions to improve understanding of both canine olfaction and electronic nose technology.

Shahi MH, York D, Gandour-Edwards R, et al.
BMI1 is expressed in canine osteosarcoma and contributes to cell growth and chemotherapy resistance.
PLoS One. 2015; 10(6):e0131006 [PubMed] Free Access to Full Article Related Publications
BMI1, a stem cell factor and member of the polycomb group of genes, has been shown to contribute to growth and chemoresistance of several human malignancies including primary osteosarcoma (OSA). Naturally occurring OSA in the dog represents a large animal model of human OSA, however the potential role of BMI1 in canine primary and metastatic OSA has not been examined. Immunohistochemical staining of canine primary and metastatic OSA tumors revealed strong nuclear expression of BMI1. An identical staining pattern was found in both primary and metastatic human OSA tissues. Canine OSA cell lines (Abrams, Moresco, and D17) expressed high levels of BMI1 compared with canine osteoblasts and knockdown or inhibition of BMI1 by siRNA or by small molecule BMI1-inhibitor PTC-209 demonstrated a role for BMI1 in canine OSA cell growth and resistance to carboplatin and doxorubicin chemotherapy. These findings suggest that inhibition of BMI1 in primary or metastatic OSA may improve response to chemotherapy and that the dog may serve as a large animal model to evaluate such therapy.

Burrai GP, Tanca A, De Miglio MR, et al.
Investigation of HER2 expression in canine mammary tumors by antibody-based, transcriptomic and mass spectrometry analysis: is the dog a suitable animal model for human breast cancer?
Tumour Biol. 2015; 36(11):9083-91 [PubMed] Related Publications
Canine mammary tumors (CMTs) share many features with human breast cancer (HBC), specifically concerning cancer-related pathways. Although the human epidermal growth factor receptor 2 (HER2) plays a significant role as a therapeutic and prognostic biomarker in HBC, its relevance in the pathogenesis and prognosis of CMT is still controversial. The aim of this study was to investigate HER2 expression in canine mammary hyperplasic and neoplastic tissues as well as to evaluate the specificity of the most commonly used polyclonal anti HER2 antibody by multiple molecular approaches. HER2 protein and RNA expression were determined by immunohistochemistry (IHC) and by quantitative real-time (qRT) PCR. A strong cell membrane associated with non-specific cytoplasmic staining was observed in 22% of carcinomas by IHC. Adenomas and carcinomas exhibited a significantly higher HER2 mRNA expression when compared to normal mammary glands, although no significant difference between benign and malignant tumors was noticed by qRT-PCR. The IHC results suggest a lack of specificity of the FDA-approved antibody in CMT samples as further demonstrated by Western immunoblotting (WB) and reverse phase protein arrays (RPPA). Furthemore, HER2 was not detected by mass spectrometry (MS) in a protein-expressing carcinoma at the IHC investigation. This study highlights that caution needs to be used when trying to translate from human to veterinary medicine information concerning cancer-related biomarkers and pathways. Further investigations are necessary to carefully assess the diagnostic and biological role specifically exerted by HER2 in CMTs and the use of canine mammary tumors as a model of HER2 over-expressing breast cancer.

Schiffman JD, Breen M
Comparative oncology: what dogs and other species can teach us about humans with cancer.
Philos Trans R Soc Lond B Biol Sci. 2015; 370(1673) [PubMed] Article available free on PMC after 19/07/2016 Related Publications
Over 1.66 million humans (approx. 500/100,000 population rate) and over 4.2 million dogs (approx. 5300/100,000 population rate) are diagnosed with cancer annually in the USA. The interdisciplinary field of comparative oncology offers a unique and strong opportunity to learn more about universal cancer risk and development through epidemiology, genetic and genomic investigations. Working across species, researchers from human and veterinary medicine can combine scientific findings to understand more quickly the origins of cancer and translate these findings to novel therapies to benefit both human and animals. This review begins with the genetic origins of canines and their advantage in cancer research. We next focus on recent findings in comparative oncology related to inherited, or genetic, risk for tumour development. We then detail the somatic, or genomic, changes within tumours and the similarities between species. The shared cancers between humans and dogs that we discuss include sarcoma (osteosarcoma, soft tissue sarcoma, histiocytic sarcoma, hemangiosarcoma), haematological malignancies (lymphoma, leukaemia), bladder cancer, intracranial neoplasms (meningioma, glioma) and melanoma. Tumour risk in other animal species is also briefly discussed. As the field of genomics advances, we predict that comparative oncology will continue to benefit both humans and the animals that live among us.

Mochizuki H, Kennedy K, Shapiro SG, Breen M
BRAF Mutations in Canine Cancers.
PLoS One. 2015; 10(6):e0129534 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
Activating mutations of the BRAF gene lead to constitutive activation of the MAPK pathway. Although many human cancers carry the mutated BRAF gene, this mutation has not yet been characterized in canine cancers. As human and canine cancers share molecular abnormalities, we hypothesized that BRAF gene mutations also exist in canine cancers. To test this hypothesis, we sequenced the exon 15 of BRAF, mutation hot spot of the gene, in 667 canine primary tumors and 38 control tissues. Sequencing analysis revealed that a single nucleotide T to A transversion at nucleotide 1349 occurred in 64 primary tumors (9.6%), with particularly high frequency in prostatic carcinoma (20/25, 80%) and urothelial carcinoma (30/45, 67%). This mutation results in the amino acid substitution of glutamic acid for valine at codon 450 (V450E) of canine BRAF, corresponding to the most common BRAF mutation in human cancer, V600E. The evolutional conservation of the BRAF V600E mutation highlights the importance of MAPK pathway activation in neoplasia and may offer opportunity for molecular diagnostics and targeted therapeutics for dogs bearing BRAF-mutated cancers.

DEN Otter W, Hack M, Jacobs JJ, et al.
Effective Treatment of Transmissible Venereal Tumors in Dogs with Vincristine and IL2.
Anticancer Res. 2015; 35(6):3385-91 [PubMed] Related Publications
AIM: To improve treatment of inoperable transmissible venereal tumors (TVTs) in dogs. Recently, we showed that TVT is sensitive to intratumoral treatment with interleukin-2 (IL2). In addition it is known that TVT is sensitive to intravenous treatment with vincristine. In the present study we tried to establish the therapeutic effect of intratumoral treatment with vincristine and IL2.
PATIENTS AND METHODS: We treated 12 dogs with TVT with 1-4 intratumoral treatments with vincristine and IL-2. Per treatment we used vincristine (0.5-0.7 mg/m(2)) and IL2 (2×10(6) units). The injections were given at weekly intervals.
RESULTS: Early therapeutic effects were: three complete regressions, four partial regressions, three stable disease, and two progressive disease. Late therapeutic effects were established 45-60 months after the first presentation; there were five complete regressions, no partial regressions, nor stable or progressive diseases. Interestingly, all five dogs with late therapeutic effects were in good health. No tumor recurrence was noted.
CONCLUSION: Intratumoral treatment of TVT with vincristine and IL2 appears to have impressive therapeutic effects.

Figueira AC, Gomes C, Vilhena H, et al.
Characterization of α-, β- and p120-Catenin Expression in Feline Mammary Tissues and their Relation with E- and P-Cadherin.
Anticancer Res. 2015; 35(6):3361-9 [PubMed] Related Publications
BACKGROUND: Abnormal catenin expression has been related to mammary carcinogenesis in both human and canine species and they are considered tumor- and invasion-suppressor molecules; however, in feline mammary tissues they have been scarcely studied.
MATERIALS AND METHODS: The immunohistochemical expression of α-, β- and p120-catenin was studied in a series of normal feline mammary glands, hyperplastic/dysplastic lesions and benign and malignant mammary tumors. Their relationship with clinicopathological parameters and with E- and P-cadherin expression was assessed.
RESULTS: Normal tissues, hyperplastic/dysplastic lesions and benign tumors expressed α-, β- and p120-catenin in the membrane of more than 75% of the luminal epithelial cells, while in malignant tumors, there was a reduction in their membranous expression and a p120-catenin cytoplasmic expression in 40%. Reduced α-catenin expression was related to tumor features with prognostic value, namely tumor size (p=0.0203) and necrosis (p=0.0205). The expression of α-, β- and p120-catenin were individually related to each other and collectively associated with E-cadherin expression.
CONCLUSION: The results demonstrate a relationship between feline mammary carcinogenesis and decreased expression of catenins, suggesting that they may represent a valuable tool in the diagnosis of feline mammary neoplasms.

Knapp DW, Dhawan D, Ostrander E
"Lassie," "Toto," and fellow pet dogs: poised to lead the way for advances in cancer prevention.
Am Soc Clin Oncol Educ Book. 2015; :e667-72 [PubMed] Related Publications
Cancer causes substantial morbidity and takes the lives of over 8 million people worldwide each year. Advances in cancer prevention research are crucial, and animal models are key to this. There are many valuable experimentally induced cancer models, but these do not fully meet the needs for cancer prevention studies. Pet dogs with risks for naturally occurring cancer can fill important gaps in cancer prevention research. Using invasive urothelial carcinoma (iUC) as an example, the advantages of utilizing pet dogs include: (1) close similarities between dogs and humans in carcinogenesis, molecular and cellular features, invasive and metastatic behavior, and response to treatment, thus providing high relevance for comparative studies, (2) shared environment between dogs and humans to help identify not-yet-known environmental iUC risks, (3) strong breed-associated risk (5- to 21-fold increased risk compared with mixed breeds) that facilitates investigation of gene-environment interactions, screening, and early intervention, (4) large size of dogs (versus rodents) that allows collection of fluids and tissues via cystoscopy, and detailed imaging at multiple time points, and (5) acceptance for studies in which each participating dog can benefit while enjoying life in their family environment, and in which findings will help other dogs and humans. An ongoing 3-year study in Scottish Terriers (comparable to a 15- to 20-year study in humans) is aimed at defining genetic and environmental risk factors for iUC, effective methods for screening/early detection, and a successful secondary cancer prevention approach with very promising results to date. Pet dogs can indeed propel cancer prevention research.

Carvalho MI, Pires I, Prada J, et al.
Positive Interplay Between CD3+ T-lymphocytes and Concurrent COX-2/EGFR Expression in Canine Malignant Mammary Tumors.
Anticancer Res. 2015; 35(5):2915-20 [PubMed] Related Publications
BACKGROUND/AIM: The ability of tumors to evade the immune system is one of cancer hallmarks. In breast cancer, it has been demonstrated that the cyclooxygenase-2(+)/ epidermal growth factor receptor(+) (COX-2(+)/EGFR(+)) status might influence tumor microenvironment allowing escape of cancer cells to the immune system. This topic is unknown in canine mammary tumors (CMT). Therefore, the potential relationship between CD3(+) T-lymphocytes and concurrent COX-2/EGFR expression was investigated.
MATERIALS AND METHODS: Formalin-fixed paraffin-embedded malignant CMT samples (n=63) were submitted to immunohistochemical staining to detect CD3, COX-2 and EGFR.
RESULTS: Tumoral CD3(+) T-lymphocytes were significantly associated with tubular differentiation grade (p=0.006), tumor necrosis (p=0.025), histological grade of malignancy (p=0.027) and presence of lymph node metastasis (p=0.009). A correlation between COX-2 and EGFR was observed (r=0.741, p<0.0001). The COX-2(+)/EGFR(+) group was associated with tumor size (p=0.002), mitotic index (p=0.019), histological grade of malignancy (p=0.035) and presence of lymph node metastasis (p=0.041). CD3(+) T-lymphocytes and COX-2/EGFR groups were significantly associated (p=0.025) and positively correlated (r=0.399; p=0.003).
CONCLUSION: The present results suggest that the COX-2(+)/EGFR(+) status may be part of a strategy adopted by tumor cells to evade the cytotoxic tumor-specific immune responses.

Liu W, Selçuk F, Rütgen BC, et al.
Evaluation of Stem Cell Marker Expression in Canine B-Cell Lymphoma Cell Lines, B-Cell Lymphoma-generated Spheres and Primary Samples.
Anticancer Res. 2015; 35(5):2805-16 [PubMed] Related Publications
BACKGROUND: Canine lymphoma has lately drawn focus as a model of human non-Hodgkin's lymphoma due to its spontaneous occurrence and similar biological behavior. Cells with stem cell-like characteristics are believed to play a key role in therapeutic failure. Thus, an initial characterization and the possibility of specific detection of such cells could bear significant value.
MATERIALS AND METHODS: Expression of 12 stem cell markers were analyzed in two canine B-cell lymphoma cell lines, their generated spheres, and in primary lymphoma samples by quantitative real-time polymerase chain reaction and partially by flow cytometry and immunocytochemistry.
RESULTS: Expression of maternal embryonic leucine zipper kinase (Melk) was significantly higher in CLBL-1, CLBL-1M and in primary B-cell lymphoma samples compared to non-neoplastic lymph nodes. Spheres displayed a higher expression of v-myc myelocytomatosis viral oncogene homolog (Myc) and lower expression of Cd44 compared to original cell lines and primary B-cell lymphoma samples.
CONCLUSION: The results suggest a potential interesting role of Melk in canine B-cell lymphoma. Furthermore, the up-regulation of Myc in serum-free-generated spheres offers interesting possibilities for functional assays characterizing the specific generated sub-population.

Angelopoulou K, Karagiannis GS
Identification, Molecular Characterization and Alternative Splicing of Three Novel Members of the Canine Kallikrein (Klk)-related Peptidase Family.
Anticancer Res. 2015; 35(5):2715-23 [PubMed] Related Publications
BACKGROUND/AIM: Kallikrein-related peptidases (KLKs) comprise a serine protease family with prominent roles in tissue physiology and disease pathogenesis, including cancer. Previously, we have characterized canine Klk4-10 and -14. Herein, we continue our efforts by characterizing three novel members of the canine family, i.e. Klk11-13, and investigating their expression in mammary cancer.
MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and DNA sequencing were used for investigating the expression and determining the nucleotide sequence of all transcripts identified, respectively.
RESULTS: It was demonstrated that (i) unlike other Klks, (CANFA)Klk12 probably possesses a non-AUG translation initiation codon, (ii) all three Klks undergo alternative splicing, with exon 2 and 3 concurrent elimination serving as the most prominent event, (iii) all transcripts identified were detected in both tumor and normal tissues, yet with different frequencies.
CONCLUSION: Having completed this work, Klk15 is the only gene remaining to experimentally resolve the entire canine Klk family. Our data lay sufficient groundwork for validation studies and await further incorporation into genetic/evolutionary studies with translational impact.

Borge KS, Nord S, Van Loo P, et al.
Canine Mammary Tumours Are Affected by Frequent Copy Number Aberrations, including Amplification of MYC and Loss of PTEN.
PLoS One. 2015; 10(5):e0126371 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
BACKGROUND: Copy number aberrations frequently occur during the development of many cancers. Such events affect dosage of involved genes and may cause further genomic instability and progression of cancer. In this survey, canine SNP microarrays were used to study 117 canine mammary tumours from 69 dogs.
RESULTS: We found a high occurrence of copy number aberrations in canine mammary tumours, losses being more frequent than gains. Increased frequency of aberrations and loss of heterozygosity were positively correlated with increased malignancy in terms of histopathological diagnosis. One of the most highly recurrently amplified regions harbored the MYC gene. PTEN was located to a frequently lost region and also homozygously deleted in five tumours. Thus, deregulation of these genes due to copy number aberrations appears to be an important event in canine mammary tumour development. Other potential contributors to canine mammary tumour pathogenesis are COL9A3, INPP5A, CYP2E1 and RB1. The present study also shows that a more detailed analysis of chromosomal aberrations associated with histopathological parameters may aid in identifying specific genes associated with canine mammary tumour progression.
CONCLUSIONS: The high frequency of copy number aberrations is a prominent feature of canine mammary tumours as seen in other canine and human cancers. Our findings share several features with corresponding studies in human breast tumours and strengthen the dog as a suitable model organism for this disease.

Jezierski T, Walczak M, Ligor T, et al.
Study of the art: canine olfaction used for cancer detection on the basis of breath odour. Perspectives and limitations.
J Breath Res. 2015; 9(2):027001 [PubMed] Related Publications
Experimental studies using trained dogs to identify breath odour markers of human cancer, published in the recent decade, have been analyzed and compared with the authors' own results. Particular published studies differ as regards the experimental setup, kind of odour samples (breath, urine, tumor tissue, serum), sample collection methods, dogs' characteristics and dog training methods as well as in results presented in terms of detection sensitivity and specificity. Generally it can be stated that trained dogs are able to distinguish breath odour samples typical for patients with lung cancer and other cancers from samples typical for healthy humans at a 'better than by chance' rate. Dogs' indications were positively correlated with content of 2-pentanone and ethyl acetate (r = 0.97 and r = 0.85 respectively) and negatively correlated with 1-propanol and propanal in breath samples (r = -0.98 and -0.87 respectively). The canine method has some advantages as a potential cancer-screening method, due to its non-invasiveness, simplicity of odour sampling and storage, ease of testing and interpretation of results and relatively low costs. Disadvantages and limitations of this method are related to the fact that it is still not known exactly to which chemical compounds and/or their combinations the dogs react. So far it could not be confirmed that dogs are able to sniff out early preclinical cancer stages with approximately the same accuracy as already diagnosed cases. The detection accuracy may vary due to failure in conditioning of dogs, decreasing motivation or confounding factors. The dogs' performance should be systematically checked in rigorous double-blind procedures. Recommendations for methodological standardization have been proposed.

Kubota K, Sakai H, Katakami N, et al.
A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.
Ann Oncol. 2015; 26(7):1401-8 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
BACKGROUND: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL).
PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles.
RESULTS: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin.
CONCLUSION: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC.

Barbieri F, Thellung S, Ratto A, et al.
In vitro and in vivo antiproliferative activity of metformin on stem-like cells isolated from spontaneous canine mammary carcinomas: translational implications for human tumors.
BMC Cancer. 2015; 15:228 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
BACKGROUND: Cancer stem cells (CSCs) are considered the cell subpopulation responsible for breast cancer (BC) initiation, growth, and relapse. CSCs are identified as self-renewing and tumor-initiating cells, conferring resistance to chemo- and radio-therapy to several neoplasias. Nowadays, th (about 10mM)e pharmacological targeting of CSCs is considered an ineludible therapeutic goal. The antidiabetic drug metformin was reported to suppress in vitro and in vivo CSC survival in different tumors and, in particular, in BC preclinical models. However, few studies are available on primary CSC cultures derived from human postsurgical BC samples, likely because of the limited amount of tissue available after surgery. In this context, comparative oncology is acquiring a relevant role in cancer research, allowing the analysis of larger samples from spontaneous pet tumors that represent optimal models for human cancer.
METHODS: Isolation of primary canine mammary carcinoma (CMC) cells and enrichment in stem-like cell was carried out from fresh tumor specimens by culturing cells in stem-permissive conditions. Phenotypic and functional characterization of CMC-derived stem cells was performed in vitro, by assessment of self-renewal, long-lasting proliferation, marker expression, and drug sensitivity, and in vivo, by tumorigenicity experiments. Corresponding cultures of differentiated CMC cells were used as internal reference. Metformin efficacy on CMC stem cell viability was analyzed both in vitro and in vivo.
RESULTS: We identified a subpopulation of CMC cells showing human breast CSC features, including expression of specific markers (i.e. CD44, CXCR4), growth as mammospheres, and tumor-initiation in mice. These cells show resistance to doxorubicin but were highly sensitive to metformin in vitro. Finally, in vivo metformin administration significantly impaired CMC growth in NOD-SCID mice, associated with a significant depletion of CSCs.
CONCLUSIONS: Similarly to the human counterpart, CMCs contain stem-like subpopulations representing, in a comparative oncology context, a valuable translational model for human BC, and, in particular, to predict the efficacy of antitumor drugs. Moreover, metformin represents a potential CSC-selective drug for BC, as effective (neo-)adjuvant therapy to eradicate CSC in mammary carcinomas of humans and animals.

Liu W, Moulay M, Willenbrock S, et al.
Comparative characterization of stem cell marker expression, metabolic activity and resistance to doxorubicin in adherent and spheroid cells derived from the canine prostate adenocarcinoma cell line CT1258.
Anticancer Res. 2015; 35(4):1917-27 [PubMed] Related Publications
BACKGROUND: Canine prostate cancer represents a spontaneous animal model for the human counterpart. Cells with stem cell-like character are considered to play a major role in therapeutic resistance and tumor relapse. Thus, the identification of markers allowing for recognition and characterization of these cells is essential.
MATERIALS AND METHODS: Expression of 12 stem cell marker genes in the canine prostate cancer cell line CT1258 and spheroid cells generated from these was analyzed by quantitative real-time PCR. In CT1258 and the generated spheroid cells, CD44 and CD133 expression was analyzed by flow cytometry, as well as proliferation and doxorubicin resistance.
RESULTS: Integrin alpha-6 (ITGA6) expression and metabolic activity were significantly up-regulated in CT1258-derived spheroid cells, while doxorubicin resistance remained comparable.
CONCLUSION: ITGA6 de-regulation and metabolic activity appear to be characteristic of the generated spheres, indicating potential intervention targets.

Lampreht U, Kamensek U, Stimac M, et al.
Gene Electrotransfer of Canine Interleukin 12 into Canine Melanoma Cell Lines.
J Membr Biol. 2015; 248(5):909-17 [PubMed] Related Publications
A gene electrotransfer (GET) of interleukin 12 (IL-12) had already given good results when treating tumors in human and veterinary clinical trials. So far, plasmids used in veterinary clinical studies encoded a human or a feline IL-12 and an ampicillin resistance gene, which is not recommended by the regulatory agencies to be used in clinical trials. Therefore, the aim of the current study was to construct the plasmid encoding a canine IL-12 with kanamycin antibiotic resistance gene that could be used in veterinary clinical oncology. The validation of the newly constructed plasmid was carried out on canine malignant melanoma cells, which have not been used in GET studies so far, and on human malignant melanoma cells. Canine and human malignant melanoma cell lines were transfected with plasmid encoding enhanced green fluorescence protein at different pulse parameter conditions to determine the transfection efficiency and cell survival. The IL-12 expression of the most suitable conditions for GET of the plasmid encoding canine IL-12 was determined at mRNA level by the qRT-PCR and at protein level with the ELISpot assay. The obtained results showed that the newly constructed plasmid encoding canine IL-12 had similar or even higher expression capacity than the plasmid encoding human IL-12. Therefore, it represents a promising therapeutic plasmid for further IL-12 gene therapy in clinical studies for spontaneous canine tumors. Additionally, it also meets the main regulatory agencies' (FDA and EMA) criteria.

Jensen-Jarolim E, Fazekas J, Singer J, et al.
Crosstalk of carcinoembryonic antigen and transforming growth factor-β via their receptors: comparing human and canine cancer.
Cancer Immunol Immunother. 2015; 64(5):531-7 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
There is accumulating evidence that the transforming growth factor beta (TGF-β) and nuclear factor kappa-B (NFκB) pathways are tightly connected and play a key role in malignant transformation in cancer. Immune infiltration by regulatory T- and B-lymphocytes (Tregs, Bregs) has recently gained increased attention for being an important source of TGF-β. There is a plethora of studies examining the pro-tumorigenic functions of carcinoembryonic antigen (CEA), but its receptor CEAR is far less studied. So far, there is a single connecting report that TGF-β also may signal through CEAR. The crosstalk between cancer tissues is further complicated by the expression of CEAR and TGF-β receptors in stromal cells, and implications of TGF-β in epithelial-mesenchymal transition. Furthermore, tumor-infiltrating Tregs and Bregs may directly instruct cancer cells by secreting TGF-β binding to their CEAR. Therefore, both TGF-β and CEA may act synergistically in breast cancer and cause disease progression, and NFκB could be a common crossing point between their signaling. CEAR, TGF-β1-3, TGF-β-R types I-III and NFκB class I and II molecules have an outstanding human-canine sequence identity, and only a canine CEA homolog has not yet been identified. For these reasons, the dog may be a valid translational model patient for investigating the crosstalk of the interconnected CEA and TGF-β networks.

Shapiro SG, Raghunath S, Williams C, et al.
Canine urothelial carcinoma: genomically aberrant and comparatively relevant.
Chromosome Res. 2015; 23(2):311-31 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.

Decker B, Parker HG, Dhawan D, et al.
Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer--Evidence for a Relevant Model System and Urine-Based Diagnostic Test.
Mol Cancer Res. 2015; 13(6):993-1002 [PubMed] Article available free on PMC after 19/07/2016 Related Publications
UNLABELLED: Targeted cancer therapies offer great clinical promise, but treatment resistance is common, and basic research aimed at overcoming this challenge is limited by reduced genomic and biologic complexity in artificially induced rodent tumors compared with their human counterparts. Animal models that more faithfully recapitulate genotype-specific human pathology could improve the predictive value of these investigations. Here, a newly identified animal model for oncogenic BRAF-driven cancers is described. With 20,000 new cases in the United States each year, canine invasive transitional cell carcinoma of the bladder (InvTCC) is a common, naturally occurring malignancy that shares significant histologic, biologic, and clinical phenotypes with human muscle invasive bladder cancer. In order to identify somatic drivers of canine InvTCC, the complete transcriptome for multiple tumors was determined by RNAseq. All tumors harbored a somatic mutation that is homologous to the human BRAF(V600E) mutation, and an identical mutation was present in 87% of 62 additional canine InvTCC tumors. The mutation was also detectable in the urine sediments of all dogs tested with mutation-positive tumors. Functional experiments suggest that, like human tumors, canine activating BRAF mutations potently stimulate the MAPK pathway. Cell lines with the mutation have elevated levels of phosphorylated MEK, compared with a line with wild-type BRAF. This effect can be diminished through application of the BRAF(V600E) inhibitor vemurafenib. These findings set the stage for canine InvTCC as a powerful system to evaluate BRAF-targeted therapies, as well as therapies designed to overcome resistance, which could enhance treatment of both human and canine cancers
IMPLICATIONS: This study demonstrates the activating BRAF mutation (V600E), which is found in multiple human cancers, is a driver of canine InvTCC, and highlights a urine-based test for quick diagnosis.

Rue SM, Eckelman BP, Efe JA, et al.
Identification of a candidate therapeutic antibody for treatment of canine B-cell lymphoma.
Vet Immunol Immunopathol. 2015; 164(3-4):148-59 [PubMed] Related Publications
B-cell lymphoma is one of the most frequently observed non-cutaneous neoplasms in dogs. For both human and canine BCL, the standard of care treatment typically involves a combination chemotherapy, e.g. "CHOP" therapy. Treatment for human lymphoma greatly benefited from the addition of anti-CD20 targeted biological therapeutics to these chemotherapy protocols; this type of therapeutic has not been available to the veterinary oncologist. Here, we describe the generation and characterization of a rituximab-like anti-CD20 antibody intended as a candidate treatment for canine B-cell lymphoma. A panel of anti-canine CD20 monoclonal antibodies was generated using a mouse hybridoma approach. Mouse monoclonal antibody 1E4 was selected for construction of a canine chimeric molecule based on its rank ordering in a flow cytometry-based affinity assay. 1E4 binds to approximately the same location in the extracellular domain of CD20 as rituximab, and 1E4-based chimeric antibodies co-stain canine B cells in flow cytometric analysis of canine leukocytes using an anti-canine CD21 antibody. We show that two of the four reported canine IgG subclasses (cIgGB and cIgGC) can bind to canine CD16a, a receptor involved in antibody-dependent cellular cytotoxicity (ADCC). Chimeric monoclonal antibodies were assembled using canine heavy chain constant regions that incorporated the appropriate effector function along with the mouse monoclonal 1E4 anti-canine CD20 variable regions, and expressed in CHO cells. We observed that 1E4-cIgGB and 1E4-cIgGC significantly deplete B-cell levels in healthy beagle dogs. The in vivo half-life of 1E4-cIgGB in a healthy dog was ∼14 days. The antibody 1E4-cIgGB has been selected for further testing and development as an agent for the treatment of canine B-cell lymphoma.

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